Potential therapeutic applications of antler stem cells and their derivatives

Figure 1 Outcomes following pedicle periosteum deletion and membrane insertion. A: Total pedicle periosteum (PP) (arrow) deletion; B: Failure in antler regeneration from the PP-less pedicle stump (left), whereas the sham-operated pedicle regenerated a multi-branched antler (right); C: Partial PP (arrow) deletion (distal third); D: Regenerating antler bud (velvet antler) from the cut end of PP on the pedicle shaft. Note that this place is distant from the natural regeneration plane (arrow); E: Membrane (arrow) insertion between the PP and the enveloping skin in a pedicle stump; F: Scab-wrapped regenerating antler (arrow). Note that the inserted membrane prevented the pedicle skin from participating in antler regeneration, but failed to stop antler regeneration. PP: Pedicle periosteum; VA: Velvet antler; SC: Scab-wrapped regenerating antler.

Figure 2 Antlerogenic periosteum deletion and transplantation, and histological structure of a growing antler tip. A: Antlerogenic periosteum (AP) deletion (right side). Note that the deleted AP will be transplanted autologously onto the forehead region; B: Outcomes of AP deletion and transplantation. Note that the AP-less crest region failed to develop a pedicle and antler (arrow), but the transplanted forehead region initiated ectopic antler formation (arrowhead); C: Histological structure of a growing antler tip. Note that the reserve mesenchyme layer is located in the outermost position and immediately under the dermis of velvet skin. AP: Antlerogenic periosteum; D: Dermis; RM: Reserve mesenchyme; PC: Pre-cartilage; CA: Cartilage; HA: Hypertrophic cartilage; BO: Bone.

Figure 3 Simplified proposed model of signaling pathways associated with antler stem cell- and derivative-mediated tissue repair. Antler stem cells (AnSCs), antler blastema progenitor cells (ABPCs), and their cell-free derivatives regulate tissue repair through interconnected anti-fibrotic, immunomodulatory, osteochondral, angiogenic, and anti-senescence pathways. Suppression of transforming growth factor-β/SMAD signaling and the fibroblast-to-myofibroblast transition reduces alpha-smooth muscle actin expression and collagen deposition. Nuclear factor kappa B and Toll-like receptor 2 (TLR2)/TLR4 inhibition, together with context-dependent regulation of macrophage recruitment and polarization, mediates immunomodulation. Runx2/Cbfa1, Wnt/β-catenin, JUN, and the miR-140/matrix metalloproteinase-13 axis regulate bone and cartilage regeneration. PTN/PTPRZ and thymosin β10 contribute to niche regulation, angiogenesis, and chondrogenesis, whereas the miR-21-5p/signal transducer and activator of transcription 3 axis and uridine are associated with wound healing and anti-senescence activity, respectively. TGF: Transforming growth factor; α-SMA: Alpha-smooth muscle actin; AnSCs: Antler stem cells; ABPCs: Antler blastema progenitor cells; NF-κB: Nuclear factor kappa B; TLR: Toll-like receptor; STAT3: Signal transducer and activator of transcription 3; EVs: Extracellular vesicles; ECM: Extracellular matrix; MMP13: Matrix metalloproteinase-13; SASP: Senescence-associated secretory phenotype.